This invention relates to the use of a combination of a fibrinolytic and a prostacyclin analogue for thrombosis treatment, and to the corresponding combination product.
According to K. H. Gold et al. Circulation 68, I-50 to I-54 (1983) and W. Ganz et al. Amer. Heart J. 101, 4 (1981), the recurrence of thrombosis (rethrombosis) after an initially successful thrombolysis, continues to represent a problem in fibrinolytic therapy. As pathogenic mechanisms, these mention the presence of a damaged and thus a thrombogenic vascular inner wall on the originally thrombosed site after dissolution of thrombi, and in many cases a bleeding anomaly induced by stenoses. Thrombogenic surfaces and rheological disturbances result in renewed activation of the plasma clotting system and thrombocytes (platelets).
In his article "Pharmacology of Streptokinase" (from the manual "Experimental Pharmacology 46: Fibrinolytics and Antifibrinolytics, F. Markward (ed.), Springer-Verlag, Berlin-Heidelberg-New York, 1978, 151-177), H. P. Kloecking writes that, particularly after thrombolysis with streptokinase and urokinase but to a lesser extent also after use of t-PA and pro-urokinase, cleavage products of fibrinogen and fibrin occur. These result in an increased aggregation tendency of platelets and thus promote quick new growth of platelet thrombi on the original site of a lysed thrombus.
Current clinical prophylaxis of fast rethromboses involve the inhibition of plasmatic clotting by heparin. E. Hiller comments on this in the Muenchner medizin. Wochenschrift 126, 13 (1984). He considers a prophylaxis with heparin as problematic, since platelet-induced rethromboses are not thereby prevented. According to his data, these are more likely even promoted. According to Kloecking, because of the consumption of the clotting factors, the plasmatic clotting system is no longer fully functioning especially after thrombolysis with streptokinase or urokinase. By the additional administration of heparin, thus, the danger of bleeding is promoted.
To what extent platelets and to what extent the plasmatic clotting system are involved in rethrombosis is indeed often discussed but still has not been clarified.